Abstract The Cancer Genetics Program within the UNC Lineberger Comprehensive Cancer Center (LCCC) was established in 2001 to facilitate an integrated, multi-disciplinary approach to research and clinical care. It is comprised of laboratory-based investigators, statistical geneticists, researchers and clinicians, all focused on improving our understanding and treatment of cancer. By integrating the multiple strengths of UNC, ranging from basic science to clinical genomic analysis, the LCCC Genetics Program has become a world leader in using genome-scale sequencing technology to address critical clinical questions related to cancer. Treatments will increasingly be tailored to an individual's genomic constitution and genomic characteristics of their tumor, mitigating toxicity and enhancing efficacy through individually tailored treatment and precise targeting of the mutations that drive tumor propagation. We have developed a comprehensive program that includes: (i) utilizing diverse experimental organisms from yeast, worm and mouse, to cell-based systems and ultimately human populations with the overarching goal of identifying mechanisms that result in genomic changes and the specific lesions responsible for cancer phenotypes; (ii) use of Whole Genome, Whole Exome and Whole Transcriptome Sequencing (WGS/WES/WTS) as effective diagnostic tools; (iii) facilitating the effective use of genomic information by patients and providers through structured categorization of genomic variation based upon clinical validity and utility; (iv) a state-of-the-art informatics approach that incorporates generation, analysis, and management of genomic data with coupling of genomic and clinical information to drive both clinical testing and translational research; (v) development of ethical and practical policies for the use of WGS data by both patients and clinicians; and (vi) exploration of massively parallel sequencing in a public health context through sequencing of selected, highly actionable genes in members of the general population for cancer-prevention purposes. Our vision has been realized through value added LCCC resources for strategic recruitment of faculty in emerging fields, investment in cutting-edge technology, enhanced organizational capability for integrative analysis and the securing of significant federal funding to enable the application of genomics to diverse aspects of cancer care and prevention. This unified and integrated effort ensures that insights gained through basic research do not linger in the lab but will lead directly as possible to application in humans. Such an integrated approach is critical for understanding the genesis, progression, and treatment of cancer. There are 29 program members from 10 different departments (6 departments in the School of Medicine, 2 in the School of Public Health, 2 in the College of Arts and Sciences). During the last funding period, program members have published 627 cancer-related articles (36% collaborative). In 2014, our program members held 51 grants and $25.7 (total cost) in annual extramural funding, including 12 grants and $4.7M (total costs) from the NCI.